The present invention relates generally to a novel class of imidazolidinones that are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
Hepatitis C virus (HCV) is the major cause of transfusion and community-acquired non-A, non-B hepatitis worldwide. Approximately 2% of the world""s population are infected with the virus. In the Unites States, hepatitis C represents approximately 20% of cases of acute hepatitis. Unfortunately, self-limited hepatitis is not the most common course of acute HCV infection. In the majority of patients, symptoms of acute hepatitis resolve, but alanine aminotransferase (a liver enzyme diagnostic for liver damage) levels often remain elevated and HCV RNA persists. Indeed, a propensity to chroninicity is the most distinguishing characteristic of hepatitis C, occurring in at least 85% of patients with acute HCV infection. The factors that lead to chronicity in hepatitis C are not well defined. Chronic HCV infection is associated with increased incidence of liver cirrhosis and liver cancer. No vaccines are available for this virus, and current treatment is restricted to the use of alpha interferon, which is effective in only 15-20% of patients. Recent clinical studies have shown that combination therapy of alpha interferon and ribavirin leads to sustained efficacy in 40% of patients (Poynard et al. Lancet 1998, 352, 1426-1432.). However, a majority of patients still either fail to respond or relapse after completion of therapy. Thus, there is a clear need to develop more effective therapeutics for treatment of HCV-associated hepatitis.
HCV is a positive-stranded RNA virus. Based on comparison of deduced amino acid sequence and the extensive similarity in the 5xe2x80x2 untranslated region, HCV has been classified as a separate genus in the Flaviviridae family, which also includes flaviviruses such as yellow fever virus and animal pestiviruses like bovine viral diarrhea virus and swine fever virus. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.
Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.
The RNA genome is about 9.6 Kb in length, and encodes a single polypeptide of about 3000 amino acids. The 5xe2x80x2 untranslated region contains an internal ribosome entry site (IRES), which directs cellular ribosomes to the correct AUG for initiation of translation. As was determined by transient expression of cloned HCV cDNAs, the precursor protein is cotranslationally and posttranslationally processed into at least 10 viral structural and nonstructural (NS) proteins by the action of a host signal peptidase and by two distinct viral proteinase activities. The translated product contains the following proteins: core-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B.
The N-terminal portion of NS3 functions as a proteolytic enzyme that is responsible for the cleavage of sites liberating the nonstructural proteins NS4A, NS4B, NS5A, and NS5B. NS3 has further been shown to be a serine protease. Although the functions of the NS proteins are not completely defined, it is known that NS4A is a protease cofactor and NS5B is an RNA polymerase involved in viral replication. Thus agents that inhibit NS3 proteolytic processing of the viral polyprotein are expected to have antiviral activity.
There are several patents that disclose HCV NS3 protease inhibitors. WO98/17679 describes peptide and peptidomimetic ihibitors with the following formula: U-E8-E7-E6-E5-E4-NHxe2x80x94CH(CH2G1)xe2x80x94W1, where W is one of a variety of electrophilic groups, including boronic acid or ester. E4 represents either an amino acid or one of a series of peptidomimetic groups, the sythesis of which are not exemplified. HCV protease inhibitors described in the present case are not covered.
Based on the large number of persons currently infected with HCV and the limited treatments available, it is desirable to discover new inhibitors of HCV NS3 protease.
One object of the present invention is to provide compounds, or pharmaceutically acceptable salt forms or prodrugs thereof, which are useful as inhibitors of hepatitis C virus protease, more specifically, the NS3 protease.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt form or prodrug thereof.
It is another object of the present invention to provide a method for the treatment or prevention of HCV comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt form or prodrug thereof.
These and other objects of the invention, which will become apparent during the following detailed description, have been achieved by the discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt forms or prodrugs thereof, wherein R1, R2, R3, W, A1 and A2 are defined below, are effective inhibitors of HCV NS3 protease.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HCV NS3 protease, HCV growth, or both.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of HCV.
[1] Thus, in one embodiment, the present invention provides a compound of Formula (I): 
or a stereoisomer, pharmaceutically acceptable salt form or prodrug thereof, wherein:
A1 is C1-C3 alkylene substituted by 0-2 C1-C4 alkyl;
A2 is xe2x80x94C(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94CONHR9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)OR9b;
-A3-R9a;
-A3-A4-R9a;
-A3-A4-A5-R9a; or
-A3-A4-A5-A6-R9a;
W is selected from the group:
xe2x80x94B(OR26) (OR27),
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)-Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NH-Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94O-Q,
xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NH-Q,
xe2x80x94C(xe2x95x90O)CF3,
xe2x80x94C (xe2x95x90O)CF2CF3,
xe2x80x94C(xe2x95x90O)H, and
xe2x80x94C(xe2x95x90O)W1;
W1 is OR8 or xe2x80x94NR11R11a;
Q is selected from the group:
xe2x80x94(CR10R10c)m-Q1,
xe2x80x94(CR10R10c)m-Q2,
C1-C4 alkyl substituted with Q1,
C2-C4 alkenyl substituted with Q1,
C2-C4 alkynyl substituted with Q1,
an amino acid residue,
-A7-A8, and
-A7-A8-A9;
m is 1, 2, 3, or 4;
Q1 is selected from the group:
xe2x80x94CO2R11, xe2x80x94SO2R11, xe2x80x94SO3R11, xe2x80x94P(O)2R11, xe2x80x94P(O)3R11;
aryl substituted with 0-4 Q1a; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 Q1a;
Q1a is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)NR19R19a, xe2x80x94NHC(xe2x95x90O)R19, xe2x80x94SO2R19, SO2NR19R19a, NR19R19a, xe2x80x94OR19, xe2x80x94SR19, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
Q2 is xe2x80x94Xxe2x80x94NR12-Z, xe2x80x94NR12xe2x80x94Y-Z, or xe2x80x94Xxe2x80x94NR12xe2x80x94Y-Z;
X is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, or
Y is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94P(O)xe2x80x94, xe2x80x94P(O)2xe2x80x94, or xe2x80x94P(O)3xe2x80x94;
Z is selected from the group:
C1-C4 haloalkyl;
C1-C4 alkyl substituted with 0-3 Za;
C2-C4 alkenyl substituted with 0-3 Za;
C2-C4 alkynyl substituted with 0-3 Za;
C3-C10 cycloalkyl substituted with 0-5 Zb;
aryl substituted with 0-5 Zb;
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zb;
an amino acid residue;
-A7-A8, and
-A7-A8-A9;
Za is selected from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR2OR20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR2OR20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR2OR20a, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-5 Zb;
C3-C1O carbocyle substituted with 0-5 Zb;
aryl substituted with 0-5 Zb; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zb;
Zb is selected from the group:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20xe2x80x94C(xe2x95x90O)NR2OR20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20OR20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR0R20a, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy;
C3-C10 cycloalkyl substituted with 0-5 Zc;
C3-C10 carbocyle substituted with 0-5 Zc;
aryl substituted with 0-5 Zc; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 Zc;
Zc is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R20, xe2x80x94C(xe2x95x90O)NR20R20a, xe2x80x94NHC(xe2x95x90O)R20, xe2x80x94NR20R20a, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94S(xe2x95x90O)R20, xe2x80x94SO2R20, xe2x80x94SO2NR20R20a, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
R1 is selected from the group: H, F;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C2-C6 alkynyl substituted with 0-3 R1a; and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C(xe2x95x90O)NHR1b, xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl);
C1-C4 alkyl substituted with 0-3 R1c;
aryl substituted with 0-5 R1c;
xe2x80x94Oxe2x80x94(CH2)n-aryl substituted with 0-5 R1c;
xe2x80x94Sxe2x80x94(CH2)n-aryl substituted with 0-5 R1c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R1c;
n is 0, 1 or 2;
R1b is H;
C1-C4 alkyl substituted with 0-3 R1c;
C2-C4 alkenyl substituted with 0-3 R1c;
C2-C4 alkynyl substituted with 0-3 R1c;
C3-C6 cycloalkyl substituted with 0-5 R1c;
aryl substituted with 0-5 R1c;
aryl-C1-C4 alkyl substituted with 0-4 R1c; or
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group:
O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90OR1d, xe2x80x94NR1dR1d, xe2x80x94SO2R1d, xe2x80x94SO3R1d, xe2x80x94C(xe2x95x90O)NHR1d, xe2x80x94NHC(xe2x95x90O)R1d, xe2x80x94SO2NHR1d, xe2x80x94CF3, xe2x80x94OCF3, C3-C6 cycloalkyl, phenyl, and benzyl;
R1d is selected at each occurrence from the group: H, C1-C4 alkyl, phenyl and benzyl;
R2 is selected from the group: H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, and C3-C4 cycloalkyl(C1-C4 alkyl)-;
alternatively, R1 and R2 can be combined to form a 4-7 membered cyclic group consisting of carbon atoms; substituted with 0-2 R14;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C (xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHS(xcx9c0)2xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94S(xe2x95x90O)2NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O) xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0, 1, or 2;
R4 is selected from the group:
C1-C6 alkyl substituted with 0-3 R4a;
C2-C6 alkenyl substituted with 0-3 R4a;
C2-C6 alkynyl substituted with 0-3 R4a;
C3-C10 cycloalkyl substituted with 0-4 R4b;
C3-C10 carbocycle substituted with 0-4 R4b;
aryl substituted with 0-5 R4b;
aryl-C1-C4 alkyl substituted with 0-5 R4b; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R4b;
R4a is, at each occurrence, independently selected from: H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4b;
C2-C4 alkenyl substituted with 0-3 R4b;
C2-C4 alkynyl substituted with 0-3 R4b;
C3-C7 cycloalkyl substituted with 0-4 R4c;
C3-C10 carbocycle substituted with 0-4 R4c;
aryl substituted with 0-5 R4c; and
5-10 membered heterocyclic group consisting of carbon
atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4c;
C2-C4 alkenyl substituted with 0-3 R4c;
C2-C4 alkynyl substituted with 0-3 R4c;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11xe2x80x94SO2NR11R11a,
C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-3 R4d;
C2-C4 alkenyl substituted with 0-3 R4d;
C2-C4 alkynyl substituted with 0-3 R4d;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(↑O)R11, NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R8 is H or C1-C4 alkyl;
R9a is selected from the group: H, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94C(xe2x95x90O)OR9b, xe2x80x94C(xe2x95x90O)NHR9b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R9b;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
C3-C14 carbocycle substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9b is selected from the group: H;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
C3-C14 carbocycle substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, c(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C6 alkyl substituted with 0-3 R9d;
C2-C6 alkenyl substituted with 0-3 R9d;
C2-C6 alkynyl substituted with 0-3 R9d;
C3-C6 cycloalkyl substituted with 0-3 R9e;
C3-C14 carbocycle substituted with 0-4 R9e;
aryl substituted with 0-5 R9e; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9e;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-3 R9e;
C1-C4 alkoxy substituted with 0-3 R9e;
C3-C6 cycloalkyl substituted with 0-3 R9e;
aryl substituted with 0-5 R9e; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R9e;
R9e is selected at each occurrence from the group:
C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, phenyl, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R10 is selected from the group: xe2x80x94CO2R11, xe2x80x94NR11R11a, and C1-C6 alkyl substituted with 0-1 R10a;
R10a is selected from the group: halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, and aryl substituted with 0-1 R10b;
R10b is selected from the group: xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, and xe2x80x94C(xe2x95x90NH)NH2;
R10c is H or C1-C4 alkyl;
alternatively, R10 and R10c can be combined to form a C3-C6 cycloalkyl group substituted with 0-1 R10a;
R11 and R11a are, at each occurrence, independently selected from the group: H;
C1-C6 alkyl substituted with 0-3 R11b;
C2-C6 alkenyl substituted with 0-3 R11b;
C2-C6 alkynyl substituted with 0-3 R11b;
C3-C7 cycloalkyl substituted with 0-3 R11b;
aryl substituted with 0-3 R11b; and
aryl(C1-C4 alkyl)-substituted with 0-3 R11b;
R11b is OH, C1-C4 alkoxy, F, Cl, Br, I, NH2, or xe2x80x94NH(C1-C4 alkyl);
R12 is H or C1-C4 alkyl;
R14 is C1-C4 alkyl or C2-C4 alkenyl;
R19 and R19a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl), C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl);
alternatively, NR19R19a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
R20 and R20a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl)-, C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl)-;
alternatively, NR20R20a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) C1-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
f) a cyclic boronic amide where said boronic amide contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O; or
g) a cyclic boronic amide-ester where said boronic amide-ester contains from 2 to 20 carbon atoms and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R28 and R29, are independently selected from: H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
A3, A4, A5, A6, A7, A8, and A9 are independently selected from an amino acid residue; and
an amino acid residue, at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration.
[2] In another embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
A2 is xe2x80x94C(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94CONHR9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)OR9b;
xe2x80x94A3xe2x80x94R9a;
xe2x80x94A3xe2x80x94A4xe2x80x94R9a;
xe2x80x94A3xe2x80x94A4xe2x80x94A5xe2x80x94R9a; or
xe2x80x94A3xe2x80x94A4xe2x80x94A5xe2x80x94A6xe2x80x94R9a;
W is selected from the group:
xe2x80x94B(OR26)(OR27),
xe2x80x94C (xe2x95x90O)C(xe2x95x90O)xe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94Oxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF2C(xe2x95x90O)NHxe2x80x94Q,
xe2x80x94C(xe2x95x90O)CF3,
xe2x80x94C (xe2x95x90O)CF2CF3,
xe2x80x94C(xe2x95x90O)H, and
xe2x80x94C(xe2x95x90O)W1;
W1 is OR8 or xe2x80x94NR11R11a;
Q is selected from the group:
xe2x80x94(CR10R10c)mxe2x80x94Q1,
C1-C4 alkyl substituted with Q1,
C2-C4 alkenyl substituted with Q1, and
C2-C4 alkynyl substituted with Q1;
m is 1 or 2;
Q1 is selected from the group:
xe2x80x94CO2R11, xe2x80x94SO2R11, xe2x80x94SO3R11, xe2x80x94P(O)2R11, xe2x80x94P(O)3R11;
phenyl substituted with 0-4 Q1a; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 Q1a;
Q1a is H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CO2R19, xe2x80x94C(xe2x95x90O)NR19R19a, xe2x80x94NHC(xe2x95x90O)R19, xe2x80x94SO2R19, SO2NR19R19a, xe2x80x94NR19R19a, xe2x80x94OR19, xe2x80x94SR19, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
R1 is selected from the group: H, F;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C2-C6 alkynyl substituted with 0-3 R1a; and
C3-C6 cycloalkyl substituted with 0-3 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, I, CF3, CHF2, OH, xe2x95x90O, SH, xe2x80x94CO2R1b, xe2x80x94SO2R1b, xe2x80x94SO3R1b, P(O)2R1b, xe2x80x94P(O)3R1b, xe2x80x94C(xe2x95x90O)NHR1b,
xe2x80x94NHC(xe2x95x90O)R1b, xe2x80x94SO2NHR1b, xe2x80x94OR1b, xe2x80x94SR1b, C3-C6 cycloalkyl, C1-C6 alkoxy, xe2x80x94Sxe2x80x94(C1-C6 alkyl);
C1-C4 alkyl substituted with 0-3 R1c;
aryl substituted with 0-5 R1c;
xe2x80x94Oxe2x80x94(CH2)n-aryl substituted with 0-5 R1c;
xe2x80x94Sxe2x80x94(CH2)n-aryl substituted with 0-5 R1c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R1c;
n is 0, 1 or 2;
R1b is H;
C1-C4 alkyl substituted with 0-3 R1c;
C2-C4 alkenyl substituted with 0-3 R1c;
C2-C4 alkynyl substituted with 0-3 R1c;
C3-C6 cycloalkyl substituted with 0-5 R1c;
aryl substituted with 0-5 R1c;
aryl-C1-C4 alkyl substituted with 0-4 R1c; or
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94R1dR1d, xe2x80x94SO2R1d, xe2x80x94SO3R1d, xe2x80x94C(xe2x95x90O)NHR1d, xe2x80x94NHC(xe2x95x90O)R1d, xe2x80x94SO2NHR1d, xe2x80x94CF3, xe2x80x94OCF3, C3-C6 cycloalkyl, phenyl, and benzyl;
R1d is selected at each occurrence from the group: H, C1-C4 alkyl, phenyl and benzyl;
R2 is selected from the group: H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 cycloalkyl, and C3-C4 cycloalkyl(C1-C4 alkyl)-; alternatively, R1 and R2 can be combined to form a 4-7 membered cyclic group consisting of carbon atoms; substituted with 0-2 R14;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHS(xe2x95x90O)2xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94S(xe2x95x90O)2NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0, 1, or 2;
R4 is selected from the group:
C1-C6 alkyl substituted with 0-3 R4a;
C2-C6 alkenyl substituted with 0-3 R4a;
C2-C6 alkynyl substituted with 0-3 R4a;
C3-C10 cycloalkyl substituted with 0-4 R4b;
C3-C1O carbocycle substituted with 0-4 R4b;
aryl substituted with 0-5 R4b;
aryl-C1-C4 alkyl substituted with 0-5 R4b; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4b;
C2-C4 alkenyl substituted with 0-3 R4b;
C2-C4 alkynyl substituted with 0-3 R4b;
C3-C7 cycloalkyl substituted with 0-4 R4c;
C3-C10 carbocycle substituted with 0-4 R4c;
aryl substituted with 0-5 R4c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from: H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, OC(xe2x95x90O)NR11R11a, NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4c;
C2-C4 alkenyl substituted with 0-3 R4c;
C2-C4 alkynyl substituted with 0-3 R4c;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90OCO)R11, xe2x80x94NR11R11a, OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, SO2NR11R11a,
C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-3 R4d;
C2-C4 alkenyl substituted with 0-3 R4d;
C2-C4 alkynyl substituted with 0-3 R4d;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R8 is H or C1-C4 alkyl;
R9a is selected from the group: H, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94C(xe2x95x90O)OR9b, xe2x80x94C(xe2x95x90O)NHR9b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R9b;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
C3-C14 carbocycle substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9b is selected from the group: H;
C1-C6 alkyl substituted with 0-3 R9c;
C2-C6 alkenyl substituted with 0-3 R9c;
C2-C6 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
C3-C14 carbocycle substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C6 alkyl substituted with 0-3 R9d;
C2-C6 alkenyl substituted with 0-3 R9d;
C2-C6 alkynyl substituted with 0-3 R9d;
C3-C6 cycloalkyl substituted with 0-3 R9e;
C3-C14 carbocycle substituted with 0-4 R9e;
aryl substituted with 0-5 R9e; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9e;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-3 R9e;
C1-C4 alkoxy substituted with 0-3 R9e;
C3-C6 cycloalkyl substituted with 0-3 R9e;
aryl substituted with 0-5 R9e; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R9e;
R9e is selected at each occurrence from the group:
C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, phenyl, C(O)O11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R10 is selected from the group: xe2x80x94CO2R11, xe2x80x94NR11R11a, and C1-C6 alkyl substituted with 0-1 R10a;
R10a is selected from the group: halo, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94CO2R11, NR11R11a, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94C(xe2x95x90NH)NH2, and aryl substituted with 0-1 R10b;
R10b is selected from the group: xe2x80x94CO2H, xe2x80x94NH2, xe2x80x94OH, xe2x80x94SH, and xe2x80x94C(xe2x95x90NH)NH2;
R10c is H or C1-C4 alkyl;
alternatively, R10 and R10c can be combined to form a C3-C6 cycloalkyl group substituted with 0-1 R10a;
R11 and R11a are, at each occurrence, independently selected from the group: H;
C1-C6 alkyl substituted with 0-3 R11b;
C2-C6 alkenyl substituted with 0-3 R11b;
C2-C6 alkynyl substituted with 0-3 R11b;
C3-C7 cycloalkyl substituted with 0-3 R11b;
aryl substituted with 0-3 R11b; and
aryl(C1-C4 alkyl)-substituted with 0-3 R11b;
R11b is OH, C1-C4 alkoxy, F, Cl, Br, I, NH2, or xe2x80x94NH(C1-C4 alkyl);
R12 is H or C1-C4 alkyl;
R14 is C1-C4 alkyl or C2-C4 alkenyl;
R19 and R19a are independently selected from the group: H, C1-C4 alkyl, C1-C4 haloalkyl, aryl, aryl(C1-C4 alkyl), C3-C6 cycloalkyl, and C3-C6 cycloalkyl(C1-C4 alkyl);
alternatively, NR19R19a may form a 5-6 membered heterocyclic group consisting of carbon atoms, a nitrogen atom, and optionally a second heteroatom selected from the group: O, S, and N;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
b) xe2x80x94F,
c) xe2x80x94NR28R29,
d) C1-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, 1, 2, or 3 heteroatoms which can be N, S, or O;
R28 and R29, are independently selected from: H, C1-C4 alkyl, aryl(C1-C4 alkyl)-, and C3-C7 cycloalkyl;
A3, A4, A5, and A6, are independently selected from an amino acid residue; and
an amino acid residue, at each occurence, independently comprises a natural amino acid, a modified amino acid or an unnatural amino acid wherein said natural, modified or unnatural amino acid is of either D or L configuration.
[3] In an alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
A2 is xe2x80x94C(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94CONHR9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)OR9b;
xe2x80x94A3xe2x80x94R9a;
xe2x80x94A3xe2x80x94A4xe2x80x94R9a; or
xe2x80x94A3xe2x80x94A4xe2x80x94A5xe2x80x94R9a;
W is xe2x80x94B(OR26)(OR27);
R1 is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R1a;
C2-C4 alkenyl substituted with 0-2 R1a;
C2-C4 alkynyl substituted with 0-2 R1a; and
R1a is selected at each occurrence from the group:
Cl, F, Br, CF3, CHF2, OH, C3-C6 cycloalkyl, C1-C4 alkoxy, xe2x80x94Sxe2x80x94(C1-C4 alkyl);
C1-C4 alkyl substituted with 0-2 R1c;
aryl substituted with 0-3 R1c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R1c;
R1c is selected at each occurrence from the group:
C1-C4 alkyl, Cl, F, Br, I, OH, SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR1d, xe2x80x94C(xe2x95x90O)OR1d, xe2x80x94NR1dR1d, xe2x80x94SO2R1d, xe2x80x94SO3R1d, xe2x80x94C(xe2x95x90O)NHR1d, xe2x80x94NHC(xe2x95x90O)R1d, xe2x80x94SO2NHR1d, xe2x80x94CF3, xe2x80x94OCF3, C3-C6 cycloalkyl, phenyl, and benzyl;
R1d is selected at each occurrence from the group: H, C1-C4 alkyl, phenyl and benzyl;
R2 is H or C1-C4 alkyl;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O) xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0, 1, or 2;
R4 is selected from the group:
C1-C4 alkyl substituted with 0-3 R4a;
C2-C4 alkenyl substituted with 0-3 R4a;
C2-C4 alkynyl substituted with 0-3 R4a;
C3-C6 cycloalkyl substituted with 0-2 R4b;
aryl substituted with 0-5 R4b; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R4b;
R4a is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a;
C1-C4 alkyl substituted with 0-2 R4b;
C2-C4 alkenyl substituted with 0-2 R4b;
C2-C4 alkynyl substituted with 0-2 R4b;
C3-C7 cycloalkyl substituted with 0-3 R4c; aryl substituted with 0-5 R4c; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C (xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NHC(xe2x95x90NH)NHR11, xe2x80x94C(xe2x95x90NH)NHR11, xe2x95x90NOR11, xe2x80x94NR11C(xe2x95x90O)OR11a, OC(xe2x95x90O)NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2NR11R11a, xe2x80x94NR11SO2R11a, xe2x80x94OP(O)(OR11)2;
C1-C4 alkyl substituted with 0-3 R4c;
C2-C4 alkenyl substituted with 0-3 R4c;
C2-C4 alkynyl substituted with 0-3 R4c;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon
atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, xe2x80x94NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a,
C1-C4 haloalkyl, C1-C4 haloalkoxy;
C1-C4 alkyl substituted with 0-3 R4d;
C2-C4 alkenyl substituted with 0-3 R4d;
C2-C4 alkynyl substituted with 0-3 R4d;
C3-C6 cycloalkyl substituted with 0-4 R4d;
aryl substituted with 0-5 R4d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, NR11R11a, xe2x80x94OR11a, SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R9a is selected from the group: H, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94C(xe2x95x90O)OR9b, xe2x80x94C(xe2x95x90O)NHR9b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R9b;
C1-C4 alkyl substituted with 0-3 R9c;
C2-C4 alkenyl substituted with 0-3 R9c;
C2-C4 alkynyl substituted with 0-3 R9c;
C3-C6 cycloalkyl substituted with 0-3 R9d;
C3-C14 carbocycle substituted with 0-4 R9d;
aryl substituted with 0-5 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9d;
R9b is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R9c;
C2-C4 alkenyl substituted with 0-2 R9c;
C2-C4 alkynyl substituted with 0-2 R9c;
C3-C6 cycloalkyl substituted with 0-2 R9d;
C3-C14 carbocycle substituted with 0-3 R9d;
aryl substituted with 0-3 R9d; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-3 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-3 R9d;
C2-C4 alkenyl substituted with 0-3 R9d;
C2-C4 alkynyl substituted with 0-3 R9d;
C3-C6 cycloalkyl substituted with 0-3 R9e;
C3-C14 carbocycle substituted with 0-4 R9e;
aryl substituted with 0-5 R9e; and
5-10 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-10 membered heterocyclic group is substituted with 0-4 R9e;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-3 R9e;
C1-C4 alkoxy substituted with 0-3 R9e;
C3-C6 cycloalkyl substituted with 0-3 R9e;
aryl substituted with 0-5 R9e; and
5-6 membered heterocyclic group consisting of carbon atoms and 1-4 heteroatoms selected from the group: O, S, and N; optionally saturated, partially unsaturated or unsaturated; and said 5-6 membered heterocyclic group is substituted with 0-4 R9e;
R9e is selected at each occurrence from the group:
C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, phenyl, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R11 and R11a are, at each occurrence, independently selected from the group: H;
C1-C4 alkyl substituted with 0-1 R11b;
phenyl substituted with 0-2 R11b; and
benzyl substituted with 0-2 R11b;
R11b is OH, C1-C4 alkoxy, F, Cl, Br, I, NH2, or xe2x80x94NH(C1-C4 alkyl);
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
d) C1-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester contains from 2 to 16 carbon atoms;
A3, A4, and A5, are independently selected from an amino acid residue wherein said amino acid residue, at each occurence, is independently selected from the group:
Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, H is, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, Homolys, Phe(4-fluoro), Tpa, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Pro(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
[4] In another alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94;
A2 is xe2x80x94C(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94CONHR9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)OR9b;
xe2x80x94A3xe2x80x94R9a;
xe2x80x94A3xe2x80x94A4xe2x80x94R9a; or
xe2x80x94A3xe2x80x94A4xe2x80x94A5xe2x80x94R9a;
W is xe2x80x94B(OR26)(OR27);
R1 is selected from the group: H;
C1-C4 alkyl substituted with 0-2 R1a;
C2-C4 alkenyl substituted with 0-2 R1a;
C2-C4 alkynyl substituted with 0-2 R1a;
R1a is selected at each occurrence from the group:
Cl, F, Br, CF3, or CHF2;
R2 is H or methyl;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NH R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94Oxe2x80x94R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0 or 1;
R4 is selected from the group:
C1-C4 alkyl substituted with 0-3 R4a;
C2-C4 alkenyl substituted with 0-3 R4a;
C2-C4 alkynyl substituted with 0-3 R4a;
C3-C4 cycloalkyl substituted with 0-2 R4b;
phenyl substituted with 0-3 R4b;
naphthyl substituted with 0-3 R4b; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4b;
R4a is, at each occurrence, independently selected from: H, F, Cl, Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2R11a;
C1-C4 alkyl substituted with 0-2 R4b;
phenyl substituted with 0-3 R4c;
naphthyl substituted with 0-3 R4c; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4c;
R4b is, at each occurrence, independently selected from: H, F, Cl, Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, xe2x80x94NR11C(xe2x95x90O)NR11R11a, xe2x80x94NR11SO2R11a;
C1-C4 alkyl substituted with 0-1 R4c;
phenyl substituted with 0-3 R4d;
naphthyl substituted with 0-3 R4d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R4d;
R4c is, at each occurrence, independently selected from:
H, F, Cl, Br, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OCF3, OH, xe2x80x94CO2H, xe2x80x94C(xe2x95x90NH)NH2, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 haloalkyl, C1-C4 haloalkoxy and C1-C4 alkyl;
R4d is, at each occurrence, independently selected from:
H, F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NCS, xe2x80x94CF3, xe2x80x94OCF3, xe2x95x90O, OH, xe2x80x94CO2H, xe2x80x94CO2R11, xe2x80x94C(xe2x95x90O)NR11R11a, xe2x80x94NHC(xe2x95x90O)R11, NR11R11a, xe2x80x94OR11a, xe2x80x94SR11a, xe2x80x94C(xe2x95x90O)R11a, xe2x80x94S(xe2x95x90O)R11a, xe2x80x94SO2R11, xe2x80x94SO2NR11R11a, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, phenyl, and benzyl;
R9a is selected from the group: H, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94C(xe2x95x90O)OR9b, xe2x80x94C(xe2x95x90O)NHR9b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R9b;
C1-C4 alkyl substituted with 0-2 R9c;
C3-C12 carbocycle substituted with 0-3 R9d;
phenyl substituted with 0-3 R9d;
naphthyl substituted with 0-3 R9d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R9d;
R9b is selected from the group: H;
C1-C4 alkyl substituted with 0-1 R9c;
C2-C4 alkenyl substituted with 0-1 R9c;
C2-C4 alkynyl substituted with 0-1 R9c;
C3-C12 carbocycle substituted with 0-3 R9d;
phenyl substituted with 0-3 R9d;
naphthyl substituted with 0-3 R9d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-2 R9d;
C2-C4 alkenyl substituted with 0-2 R9d;
C2-C4 alkynyl substituted with 0-2 R9d;
C3-C6 cycloalkyl substituted with 0-2 R9e; C3-C12 carbocycle substituted with 0-3 R9e;
phenyl substituted with 0-3 R9e;
naphthyl substituted with 0-3 R9e; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-3 R9e;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, and phenyl;
R9e is selected at each occurrence from the group:
C1-C4 alkyl, C1-C4 alkoxy, CF3, OCF3, Cl, F, Br, I, xe2x95x90O, OH, phenyl, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, and NO2;
R11 and R11a are, at each occurrence, independently selected from the group: H, methyl, ethyl, propyl, butyl, phenyl and benzyl;
OR26 and OR27 are independently selected from:
a) xe2x80x94OH,
d) C1-C8 alkoxy, and
when taken together, OR26 and OR27 form:
e) a cyclic boronic ester where said cyclic boronic ester is formed from the group: pinanediol, pinacol, 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanedio, 5,6-decanediol, 1,2-dicyclohexylethanediol, diethanolamine, and 1,2-diphenyl-1,2-ethanediol;
A3 is Val, Glu, Ile, Thr, cyclohexylglycine, or cyclohexylalanine;
A4 is Val, Ile, Leu, cyclohexylglycine, cyclopropylglycine, t-butylglycine, phenylglycine, or 3,3-diphenylalanine; and
A5 is (D or L stereochemistry) Asp, Clu, Val, Ile, t-butylglycine, and Gla.
[5] In another alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94;
A2 is H, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94CONHR9b, xe2x80x94C(xe2x95x90O)OR9b;
xe2x80x94A3xe2x80x94R9a; or
xe2x80x94A3xe2x80x94A4xe2x80x94R9a;
W is pinanediol boronic ester;
R1 is H, ethyl, allyl, or 2,2-difluoro-ethyl;
R2 is H;
R3 is selected from the group: R4,
xe2x80x94(CH2)pxe2x80x94NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)Oxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHxe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94NHC(xe2x95x90O)NHC(xe2x95x90O) xe2x80x94R4,
xe2x80x94(CH2)pxe2x80x94C(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CH2)p-o-R4, and
xe2x80x94(CH2)pxe2x80x94Sxe2x80x94R4;
p is 0 or 1;
R4 is selected from the group: H, methyl, isopropyl, t-butyl, phenyl, benzyl, phenethyl, Ph-propyl, 3-Ph-2-propenyl, phenyl, 2-benzoic acid, 5-isophthalate dimethyl ester, triphenylmethyl, 1-(1-naphthyl)ethyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-ethoxyphenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 2-CF3-phenyl, 3-CF3-phenyl, 4-CF3-phenyl, 4-(trifluoromethoxy)phenyl, 4-(hydroxymethyl)phenyl, 3-cyanophenyl, 3-(acetyl)phenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-(acetyl)phenyl, 2-(methoxycarbonyl)-phenyl, 3-(methoxycarbonyl)-phenyl, 4-(methoxycarbonyl)-phenyl, 2-(ethoxycarbonyl)-phenyl, 3-(ethoxycarbonyl)-phenyl, 4-(ethoxycarbonyl)phenyl, 2-(butoxycarbonyl)phenyl, 2-(tert-butoxycarbonyl)phenyl, 4-(dimethylamino)phenyl, 2-(methylthio)phenyl, 3-(methylthio)phenyl, 4-(methylthio)phenyl, 2-(methylsulfonyl)phenyl, 3-CF3S-phenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-(benzyloxy)phenyl, 2-biphenyl, 4-biphenyl, 2,6-diisopropylphenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 5-Cl-2-methoxyphenyl, 4-F-2-nitrophenyl, 3,4,5,-trimethoxyphenyl, 5-Cl-2,4-dimethoxyphenyl, 5-F-2,4-dimethoxyphenyl, Trans-2-phenylcyclopropyl, 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl, 2-quinolinyl, 5-quinolinyl, 1-isoquinolinyl, 2-phenyl-4-quinolinyl, 2-phenyl-4-quinolinyl-methyl, 2-methyl-6-quinolinyl, 2-anilino-2-oxoethyl and 2-3-methylbutyric acid methyl ester;
R9a is selected from the group: H, xe2x80x94S(xe2x95x90O)R9b, xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94S(xe2x95x90O)2NHR9b, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94C(xe2x95x90O)OR9b, xe2x80x94C(xe2x95x90O)NHR9b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R9b;
C1-C4 alkyl substituted with 0-2 R9c;
C3-C12 carbocycle substituted with 0-2 R9d;
phenyl substituted with 0-2 R9d; naphthyl substituted with 0-2 R9d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-2 R9d;
R9b is selected from the group: H;
C1-C4 alkyl substituted with 0-1 R9c;
C3-C12 carbocycle substituted with 0-2 R9d;
phenyl substituted with 0-2 R9d;
naphthyl substituted with 0-2 R9d; and
5-10 membered heterocyclic group selected from the group: pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl, 4H-quinolizinyl, benzofuranyl, benzothiophenyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, and quinoxalinyl; and said 5-10 membered heterocyclic group is substituted with 0-2 R9d;
R9c is selected from the group: CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2;
C1-C4 alkyl substituted with 0-1 R9d;
C2-C4 alkenyl substituted with 0-1 R9d;
C2-C4 alkynyl substituted with 0-1 R9d; and
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, and phenyl;
R11 is selected from the group: H, methyl, ethyl, propyl, butyl, phenyl and benzyl;
A3 is Val, Glu, Ile, Thr, cyclohexylglycine, or cyclohexylalanine; and
A4 is Val, Ile, Leu, cyclohexylglycine, cyclopropylglycine, t-butylglycine, phenylglycine, or 3,3-diphenylalanine.
[6] In another alternative embodiment, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A1 is xe2x80x94CH2xe2x80x94;
A2 is xe2x80x94C(xe2x95x90O)OR9b or xe2x80x94A3xe2x80x94R9a;
W is pinanediol boronic ester;
R1 is H, ethyl or allyl;
R2 is H;
R3 is R4;
R4 is selected from the group: Ph-propyl, 3-Ph-2-propenyl, 2-phenyl-4-quinolinyl, 2-phenyl-4-quinolinyl-methyl, 2-methyl-6-quinolinyl, and 2-anilino-2-oxoethyl;
R9a is selected from the group: xe2x80x94S(xe2x95x90O)2R9b, xe2x80x94C(xe2x95x90O)R9b, xe2x80x94C(xe2x95x90O)OR9b, and xe2x80x94C(xe2x95x90O)NHR9b;
R9b is selected from the group: t-butyl, fluorenylmethyl, fluorenyl, benzyl;
phenyl substituted with 0-2 R9d;
naphthyl substituted with 0-2 R9d; and
pyridinyl substituted with 0-2 R9d;
R9d is selected at each occurrence from the group:
CF3, OCF3, Cl, F, Br, OH, C(O)OR11, NH2, NH(CH3), N(CH3)2, xe2x80x94CN, NO2, C1-C4 alkyl, C1-C4 alkoxy, and phenyl; and
A3 is Val.
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to descibe additional even more preferred embodiments of the present invention.
[7] In another alternative embodiment, the present invention provides a compound, or a stereoisomer or a pharmaceutically acceptable salt form or prodrug thereof, selected from:
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1(R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-{(2S)-3-methyl-2-[(phenylacetyl)-amino]-butanoyl)-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
tert-butyl (1S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-2-oxo-3-(3-phenylpropyl)imidazolidinyl]carbonyl}-2-methylpropylcarbamate;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3,xcex15,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-{(2S)-2-[(anilinocarbonyl)amino]-3-methylbutanoyl}-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-{(25)-2-[(9H-fluoren-1-ylcarbonyl)aminol]-3-methylbutanoyl)-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-((2S)-2-{[(4-methoxyphenyl)acetyl]amino}-3-methylbutanoyl)-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl}-3-{(2S)-2-[(9H-fluoren-1-ylcarbonyl)amino]-3-methylbutanoyl)-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
9H-fluoren-9-ylmethyl (1S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-2-oxo-3-(3-phenylpropyl)imidazolidinyl]carbonyl}-2-methylpropylcarbamate;
(4S)-N-([[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-((2S)-3-methyl-2-{[3-(trifluoromethyl)benzyl]amino}butanoyl)-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S) xe2x80x94N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-{(2S)-2-[([1,1xe2x80x2-biphenyl]-4-ylmethyl)amino]-3-methylbutanoyl}-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide; 9H-fluoren-9-ylmethyl (1S)-1-({(5S)-5-[({(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano 1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-2-oxo-3-[(2-phenyl-4-quinolinyl)methyl]imidazolidinyl)carbonyl)-2-methylpropylcarbamate;
N-((1S)-1-{[(5S)-5-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl)-amino)carbonyl]-2-oxo-3-(3-phenylpropyl)imidazolidinyl]carbonyl}-2-methylpropyl)-2-chloronicotinamide;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-{(2S)-2-[(4-butylbenzoyl)amino]-3-methylbutanoyl}-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
isobutyl (1S)-1-{[(5S)-5-([[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-2-oxo-3-(3-phenylpropyl)imidazolidinyl]carbonyl}-2-methylpropylcarbamate;
(4S)-N-{([[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-((2S)-2-([(benzoylamino)carbonyl]amino}-3-methylbutanoyl)-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S)-N-{[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-[(2S)-3-methyl-2-(1-naphthoylamino)butanoyl]-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl)-3-[(2S)-2-(acetylamino)-3-methylbutanoyl]-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
(4S)-N-{[[(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}-3-[(2S)-2-(benzoylamino)-3-methylbutanoyl]-2-oxo-1-(3-phenylpropyl)-4-imidazolidinecarboxamide;
benzyl (5S)-5-[({(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl}amino)carbonyl]-2-oxo-3-[(2E)-3-phenyl-2-propenyl]-1-imidazolidinecarboxylate; and
benzyl (5S)-5-[({(1R)-1-[(3xcex1S,4S,6S,7xcex1R)-hexahydro-3xcex1,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-butenyl}amino)carbonyl]-3-(2-anilino-2-oxoethyl)-2-oxo-1-imidazolidinecarboxylate.
This invention also provides compositions comprising one or more of the foregoing compounds and methods of using such compositions in the treatment of hepatitis C virus, such as inhibition of hepatitis C virus protease, in mammals or as reagents used as inhibitors of hepatitis C virus protease in the processing of blood to plasma for diagnostic and other commercial purposes.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a method of treating a viral infection which comprises administering to a host in need of such treatment a therapeutically effective amount of compounds of Formula (I) or pharmaceutically acceptable salt forms or prodrug thereof.
In another embodiment, the present invention provides A method of treating HCV which comprises administering to a host in need of such treatment a therapeutically effective amount of compounds of Formula (I) or pharmaceutically acceptable salt forms or prodrug thereof.
As used throughout the specification, the following abbreviations for amino acid residues or amino acids apply:
Abu is L-aminobutyric acid;
Ala is L-alanine;
Alg is L-2-amino-4-pentenoic acid;
Ape is L-2-aminopentanoic acid;
Arg is L-arginine;
Asn is L-asparagine;
Asp is L-aspartic acid;
Aze is azedine-2-carboxlic acid;
Cha is L-2-amino-3-cyclohexylpropionic acid;
Cpa is L-2-amino-3-cyclopropylpropionic acid
Cpg is L-2-amino-2-cyclopropylacetic acid;
Cys is L-cysteine;
Dfb is L-4,4xe2x80x2-difluoro-1-amino-butyric acid;
Dpa is L-2-amino-3,3-diphenylpropionic acid;
Gla is gamma-carboxyglutamic acid;
Gln is L-glutamine;
Glu is L-glutamic acid;
Gly is glycine;
H is is L-histidine;
HomoLys is L-homolysine;
Hyp is L-4-hydroxyproline;
Ile is L-isoleucine;
Irg is isothiouronium analog of L-Arg;
Leu is L-leucine;
Lys is L-lysine;
Met is L-methionine;
Orn is L-ornithine;
Phe is L-phenylalanine;
Phe(4-fluoro) is para-fluorophenylalanine;
Pro is L-proline;
Sar is L-sarcosine;
Ser is L-serine;
Thr is L-threonine;
Tpa is L-2-amino-5,5,5-trifluoropentanoic acid;
Trp is L-tryptophan;
Tyr is L-tyrosine; and
Val is L-valine.
The xe2x80x9cDxe2x80x9d prefix for the foregoing abbreviations indicates the amino acid is in the D-configuration. xe2x80x9cD,Lxe2x80x9d indicates the amino is present in mixture of the D- and the L-configuration. The prefix xe2x80x9cboroxe2x80x9d indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic ester. For example, if R1 is isopropyl and Y1 and Y2 are OH, the C-terminal residue is abbreviated xe2x80x9cboroVal-OHxe2x80x9d where xe2x80x9cxe2x80x94OHxe2x80x9d indicates the boronic acid is in the form of the free acid. The pinanediol boronic ester and the pinacol boronic ester are abbreviated xe2x80x9cxe2x80x94C10H16xe2x80x9d and xe2x80x9cxe2x80x94C6H12xe2x80x9d, respectively. Examples of other useful diols for esterification with the boronic acids are 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, and 1,2-dicyclohexylethanediol. Analogs containing sidechain substituents are described by indicating the substituent in parenthesis following the name of the parent residue. For example the analog of borophenylalanine containing a meta cyano group is -boroPhe(mCN)xe2x80x94.
The following abbreviations may also be used herein and are defined as follows. The abbreviation xe2x80x9cDIBALxe2x80x9d means diisobutylaluminum hydride. The abbreviation xe2x80x9cRaNixe2x80x9d means Raney nickel. The abbreviation xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride. The abbreviation xe2x80x9c1,1xe2x80x2-CDIxe2x80x9d means 1,1xe2x80x2-carbonyldiimidazole. The abbreviation xe2x80x9cBnxe2x80x9d means benzyl. The abbreviation xe2x80x9cBOCxe2x80x9d means t-butyl carbamate. The abbreviation xe2x80x9cCBZxe2x80x9d means benzyl carbamate. Other abbreviations are: xe2x80x9cBSAxe2x80x9d, benzene sulfonic acid; xe2x80x9cTHFxe2x80x9d, tetrahydrofuran; xe2x80x9cDMFxe2x80x9d, dimethylformamide; xe2x80x9cEDCIxe2x80x9d, 1-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; xe2x80x9cHOAtxe2x80x9d, 1-hydroxy-7-azabenzotriazole; xe2x80x9cDIEAxe2x80x9d, N,N-diisopropylethylamine; xe2x80x9cBoc-xe2x80x9d, t-butoxycarbonyl-; xe2x80x9cAc-xe2x80x9d, acetyl; xe2x80x9cpNAxe2x80x9d, p-nitro-aniline; xe2x80x9cDMAPxe2x80x9d, 4-N,N-dimethylaminopyridine; xe2x80x9cTrisxe2x80x9d, Tris(hydroxymethyl)aminomethane; xe2x80x9cPyAOPxe2x80x9d, 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate; xe2x80x9cMSxe2x80x9d, mass spectrometry; xe2x80x9cFAB/MSxe2x80x9d, fast atom bombardment mass spectrometry. LRMS(NH3-CI)and HRMS(NH3-CI)are low and high resolution mass spectrometry, respectively, using NH3 as an ion source.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. Also, it is realized that cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one skilled in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then two hydrogens on the atom are replaced.
When any variable (e.g., R4a or R11) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R4a, then said group may optionally be substituted with up to three R4a groups and R4a at each occurrence is selected independently from the definition of R4a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
xe2x80x9cAmino acid residuexe2x80x9d as used herein, refers to natural, modified or unnatural amino acids of either D- or L-configuration and means an organic compound containing both a basic amino group and an acidic carboxyl group. Natural amino acids residues are Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, H is, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 (1983), Academic Press, New York, discloses numerous suitable unnatural amino acids and is incorporated herein by reference for that purpose. Additionally, said reference describes, but does not extensively list, acylic N-alkyl and acyclic xcex1,xcex2-disubstituted amino acids. Included in the scope of the present invention are N-alkyl, aryl, and alkylaryl analogs of both in chain and N-terminal amino acid residues. Similarly, alkyl, aryl, and alkylaryl maybe substituted for the alpha hydrogen. Illustrated below are examples of N-alkyl and alpha alkyl amino acid residues, respectively. 
Modified amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, an N-CBZ-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, 3,3-diphenylalanine, naphthylalanine, phenylglycine, xcex2-phenylproline, tert-leucine, cyclohexylalanine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, t-butylglycine, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, 2-benzyl-5-aminopentanoic acid.
A list of unnatural amino acids that fall within the scope of this invention is disclosed in a PCT application PCT/US00/18655. The disclosure of which is hereby incorporated by reference. xe2x80x9cAmino acid residuexe2x80x9d also refers to various amino acids where sidechain functional groups are modified with appropriate protecting groups known to those skilled in the art. xe2x80x9cThe Peptidesxe2x80x9d, Vol 3, 3-88 (1981) discloses numerous suitable protecting groups and is incorporated herein by reference for that purpose. Examples of amino acids where sidechain functional groups are modified with appropriate protecting groups include, but are not limited to, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), and Thr(OBzl); wherein OMe is methoxy, OtBu is tert-butoxy, and OBzl is benzyloxy.
A preferred list of xe2x80x9camino acid residuexe2x80x9d in the present invention includes, but is not limited to, Ala, Arg, Asn, Asp, Aze, Cys, Gln, Glu, Gly, H is, Hyp, Ile, Leu, Lys, Met, Orn, Phe, Pro, Sar, Ser, Thr, Trp, Tyr, Val, Abu, Alg, Ape, Cha, Cpa, Cpg, Dfb, Dpa, Gla, Irg, Homol.ys, Phe(4-fluoro), Tpa, Asp(OMe), Glu(OMe), Hyp(OMe), Asp(OtBu), Glu(OtBu), Hyp(OtBu), Thr(OtBu), Asp(OBzl), Glu(OBzl), Hyp(OBzl), Thr(OBzl), cyclohexylglycine, cyclohexylalanine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
A preferred scope of substituent A3 is Val, Clu, Ile, Thr, cyclohexylglycine, and cyclohexylalanine.
A preferred scope of substituent A4 is Val, Ile, Leu, cyclohexylglycine, cyclopropylglycine, t-butylglycine, phenylglycine, and 3,3-diphenylalanine.
A preferred scope of substituent A5 is (D or L stereochemistry) Asp, Glu, Val, Ile, t-butylglycine, and Gla.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration having the specified number of carbon atoms and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbonxe2x80x94carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulpher bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CVFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include xe2x80x9cfluoroalkylxe2x80x9d which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
As used herein, xe2x80x9ccarbocyclexe2x80x9d, xe2x80x9ccarbocyclic ringxe2x80x9d, xe2x80x9ccarbocyclic groupxe2x80x9d, or xe2x80x9ccarbocyclic ring systemxe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclic groupxe2x80x9d, xe2x80x9cheterocyclic ringxe2x80x9d xe2x80x9cheterocyclic ring systemxe2x80x9d or xe2x80x9cHetxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, benzo[1,3]dioxol-yl, 2,3-dihydro-benzo[1,4]dioxin-yl, carbazolyl, 4xcex1H-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyrimidopyrimidin-yl, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred 5-10 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoxazolopyridinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9cHet-(lower alkyl)-xe2x80x9d as used herein, means a heterocyclic ring as defined above linked through a chain or branched C1-C6 alkyl group.
As used herein, the term xe2x80x9carylxe2x80x9d, or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl and naphthyl.
xe2x80x9cNH2-blocking groupxe2x80x9d as used herein, refers to various acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substitutes on these groups maybe either alkyl, aryl, alkylaryl which may contain the heteroatoms, O, S, and N as a substituent or in-chain component. A number of NH2-blocking groups are recognized by those skilled in the art of organic synthesis. By definition, an NH2-blocking group may be removable or may remain permanently bound to the NH2. Examples of suitable groups include formyl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl; aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl or adamantyloxycarbonyl. Gross and Meinhoffer, eds., The Peptides, Vol 3; 3-88 (1981), Academic Press, New York, and Greene and Wuts Protective Groups in Organic Synthesis, 315-405 (1991), J. Wiley and Sons, Inc., New York disclose numerous suitable amine protecting groups and they are incorporated herein by reference for that purpose. Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylo xycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl; 5-benzylsoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimetboxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; Nxe2x80x2-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.
As used herein, xe2x80x9ccyclic boronic esterxe2x80x9d is intended to mean a stable cyclic boronic moiety of general formula xe2x80x94B(OR)(OR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O. Cyclic boronic esters are well known in the art. Examples of cyclic boronic ester include, but are not limited to, pinanediol boronic ester, pinacol boronic ester, 1,2-ethanediol boronic ester, 1,3-propanediol boronic ester, 1,2-propanediol boronic ester, 2,3-butanediol boronic ester, 2-diisopropylethanediol boronic ester, 5,6-decanediol boronic ester, 1,2-dicyclohexylethanediol boronic ester, diethanolamine boronic ester, and 1,2-diphenyl-1,2-ethanediol boronic ester.
As used herein, xe2x80x9ccyclic boronic amidexe2x80x9d is intended to mean a stable cyclic boronic amide moiety of general formula xe2x80x94B(NR) (NR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O. Examples of cyclic boronic amide include, but are not limited to, 1,3-diaminopropane boronic amide and ethylenediamine boronic amide.
As used herein, xe2x80x9ccyclic boronic amide-esterxe2x80x9d is intended to mean a stable cyclic boronic amide-ester moiety of general formula xe2x80x94B(OR)(NR) wherein the two R substituents taken together contain from 2 to 20 carbon atoms, and optionally, 1, 2, or 3 heteroatoms which can be N, S, or O. Examples of cyclic boronic amide include, but are not limited to, 3-amino-1-propanol boronic amide-ester and ethanolamine boronic amide-ester.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9ctreatingxe2x80x9d refers to: (i) preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the s disease, disorder and/or condition.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Schemes 1-6 illustrate the synthesis of inhibitors of structure 1-9. In Schemes 1-6, A1, R3 and R9a are as defined above; L is a linker; Rxe2x80x2 and R1xe2x80x2 are H or simple alkyl or aryl, preferably methyl, ethyl, t-butyl, phenyl, or benzyl; P1, P2, P3 and P4 are nitrogen protecting groups, wherein such protecting groups are known to one skilled in the art.
In Scheme 1, substituted 2-imidazolidinone 4-carboxylic acids or esters, tetrahydro 2-pyrimidone 4-carboxylic acids or esters, and 1,3-diazepane 4-carboxylic acids or esters (1-2) can be prepared by cyclizations of commercially available materials or materials that may be easily prepared from commercially available ones (1-1). The cyclizations can be carried out with carbonyl diimidazole (Giudice, M. R.; Gatta, F.; Settimj, G.; J. Heterocycl. Chem. 1990, 27, 967), phosgene (Ellis, F.; et. al.; J. Chem. Soc., Perkin Trans 1, 1972, 1560), hexachloroacetone (Koenigsberger, K.; Prasad, K.; Repic, O.; Blacklock, T. J.; Tetrahedron: Asymmetry, 1997, 8 (14), 2347-2354), S,S-dimethyl dithiocarbonate (Leung, M.; Lai, J. -L.; Lau, K. -H.; Yu, H.; Hsiao, H. -J.; J. Org. Chem., 1996, 61 (12), 4175-4179), diphenyl carbonate or its derivatives (Eur. Pat. Appl. 629612, 21 Dec 1994), or urea (Kulinski, T.; Tkaczynski, T.; Pharmazie, 1995, 50 (12), 821-822). If Rxe2x80x2 in 1-2 is a proton, acids 1-2 need to be converted to their corresponding esters 1-2 with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used Alkylations or acylations of 1-2 with various halides or acyl halides under basic conditions can provide 1-3 (a. Jordan, T. E.; Ginsburg, S.; J. Am. Chem. Soc., 1949, 71, 2258; b. Roos, G. H. P.; Balasubramaniam, S.; Doyle, M. P.; Raab, C. E.; Synth. Commun., 1996, 26 (11), 2165-2175). An alternative way to make 1-3 from 1-2 via O-silyl ethers is treatment of 1-2 with trialkylsilyl triflate in the presence of a base, such as Et3N or lutidine, and then alkylations or acylations of the O-silyl ether intermediates with various halides or acyl halides (a. Sakaitani, Masahiro; Ohfune, Yasufumi. J. Org. Chem. 1990, 55(3), 870-6; b. Sakaitani, Masahiro; Ohfune, Yasufumi. J. Am. Chem. Soc. 1990, 112(3), 1150-8). Deprotections of P3 of 1-3 can afford 1-4 (Greene, T. W. in Protective Groups in Organic Synthesis, Ch. 7, Protection for the Amino Group, John Wiley and Sons, 2nd Ed, 1991) As described in the preparations of 1-3, alkylations or acylations of 1-4 can provide 1-5. Hydrolyses of the ester groups of 1-5 can provide acids 1-6 (Greene, T. W. Protective Groups in Organic Synthesis, Ch. 5, Protection for the Carbonyl Group, John Wiley and Sons, 2nd Ed, 1991). Peptide coupling reactions of acids 1-6 with serine traps 1-10 can afford the inhibitors 1-7 (Larock, R. C. in Comprehensive Organic Transformations: A Guide to Functional Organic Preparations, VCH Publishers, 1989, Carboxylic Acids to Amides, 972). Deprotections of P1 on the N-terminus of L provide 1-8, which can undergo peptide coupling reactions to afford the inhibitors 1-9. 
The following methods for the cyclizations, alkylations, acylations, selective protections and deprotections, hydrolyses, and coupling reactions are similar to those described above.
The inhibitors 1-9 can also be prepared from an alternative route starting from 1-5 (Scheme 1). Deprotections of the P4 in 1-5 can provide 1-6a, which can undergo peptide coupling afford the inhibitors 1-7a. Hydrolyses of the ester group in 1-7a can provide acids 1-8a, which coupled with serine traps 1-10 can afford the inhibitors 1-9.
An alternative sequence for preparing 1-5 is shown in Scheme 2. Compounds 2-2 can be prepared from N-protections of 1-2 or cyclizations of commercially available 2-2a. Selective deprotections of 2-2 or 2-2a provide 2-3 or 2-3a, respectively. 2-3a can then be converted to 2-3 by cyclizations. 1-5 can be obtained from alkylations or acylations of 2-3, followed by selective deprotections of 2-4 and then alkylations or acylations of 2-5. 
The inhibitors 1-7 can also be prepared from peptide coupling reactions of the free acids 2-2 with serine traps 1-10 as shown in Scheme 3. 3-2 can be prepared from peptide coupling reactions of 2-2 with 1-10. Amides 3-2 can be converted to imides 3-3 with (Boc)2O or CbzCl in the presence of base (Evans, D. A.; Carter, P. H.; Carreirra, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540-7552). Selective deprotections of 3-3 can give either 3-4 or 3-4a, which can be further acylated or alkylated to give 3-5 or 3-5a, respectively. 3-7 can be obtained from selective deprotections of 3-5 or 3-5a, followed by acylations or alkylations of 3-6 or 3-6a, respectively. Selective deprotections of 3-7 can provide inhibitors 1-7. 
Scheme 4 depicts an alternative synthesis of 2-4,1-5, and 1-3. Selective alkylations, acylations, or reductive aminations of 1-1 or 2-3a can give 4-1 or 4-1a, respectively. Selective deprotections, followed by alkylations, acylations, or reductive aminations of 4-1 or 4-1a, can provide 4-2. Compounds 2-4,1-5, and 1-3 can be obtained from cyclizations of 4-1a, 4-2, and 4-1, respectively. 
Other synthetic sequences for preparing 1-6 are summarized in Schemes 5 and 6. Shown in Scheme 5, coupling reactions of 2-2a with aniline can provide phenyl amides 5-1 (Evans, D. A.; Carter, P. H.; Carreirra, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540-7552). Selective deprotections of 5-1 can provide 5-2 or 5-2a. 5-4 can be obtained by conversions of 5-2 to 5-3 or 5-2a to 5-3a by alkylations, acylations, or reductive aminations, followed by selective deprotections and then by additional alkylations, acylations, or reductive aminations. Cyclizations of 5-3a, 5-4, or 5-3 can provide 5-5a, 5-6, or 5-5, respectively. 5-6 can also be obtained from selective deprotections and then alkylations or acylations of 5-5a or 5-5. An alternative way to prepare amides 5-5a or 5-5 can be via coupling reactions of aniline with 2-4 or 1-3, respectively. Amides 5-6 can be converted to the imides with Boc2O/DMAP/CH3CN, and treatment the imides with LiOH/H2O2/THF/H2O can provide the acids 1-6 (a. Evans, D. A.; Carter, P. H.; Carreirra, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540-7552; b. Gage, J. R.; Evans, D. A. Organic Syntheses 1989, 68, 83-91). 
Scheme 6 is similar to Scheme 5 Coupling reactions of 2-2 with aniline, followed by treatment of the resulting amides with (Boc)2O in the presence of a base, can provide 6-1. Selective deprotections of 6-1 can give 6-2 or 6-2a, which can undergo alkylations or acylations to form 6-3 or 6-3a, respectively. Selective deprotections of 6-3 and 6-3a can give 6-4 and 6-4a, respectively, which can then undergo additional alkylations or acylations to provide 6-5. Acids 1-6 can be obtained by treatment of imides 6-5 with LiOH/H2O2/THF/H2O. 
Compounds of the present invention containing peptide segments in A2 can be prepared from commercially available 10 materials by methods known to one skilled in the art of peptide synthesis. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/242,557, filed Oct. 23, 2000; herein incorporated in its entirety by reference.
Compounds of the present invention with other R3 can be prepared from commercially available materials by methods known to one skilled in the art of peptide synthesis. More preferably, see techniques disclosed in the U.S. Provisional Patent Application, assigned to DuPont Pharmaceuticals Co., identified as PH-7225-P1, filed simultaneously as this application.
Synthesis of Serine Traps of Structure 1-10.
a) Synthesis of xcex1-amino Boronic Ester
Scheme 7 outlines a route to mono-substituted amino boronic esters. In Scheme 7, a Grignard reagent can be reacted with a borate ester 7-1, which can be prepared by the reaction of pinanediol with trialkylborate (Elgendy, S.; Claeson, G.; Kakkar, V. V.; Green, D.; Patel, G.; Goodwin, C. A.; Baban, J. A.; Scully, M. F.; Deadman, J.; Tetrahedron 1994, 50 (12), 3803-3812), can provide boronate 7-2. Homologation of 7-2 with the anion of dichloromethane can give the xcex1-chloro boronic ester 7-3 (Matteson, D. S.; Majumdar, D. Organometallics 1983, 2, 1529-1535). Displacement of the chloride by lithium bis(trimethylsilyl)amide can give silyl amine 7-4, which is converted to the amine hydrochloride salt 7-5 with anhydrous HCl. (Matteson, D. S.; Sadhu, K. M. Organometallics 1984, 3, 1284-1288). Notice that 7-5 is shown protected as the pinanediol ester. This is the preferred protecting group, but other diol protecting groups, for example but not limited to the scope of workable and known diol protecting groups, such as pinacol, 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, 1,2-dicyclohexylethanediol, and others known to those skilled in the art are acceptable.
Peptide boronic esters can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. Peptide boronic acids and esters are generally well known in the art; however, for a general reference to synthesis of peptide boronic esters, see Kettner, C; Forsyth, T. Houben-Weyl Methods of Organic Chemistry 1999, in press; for a reference to synthesis of fluorinated peptide residues see Matassa, V. et. al., PCT Application WO 9964442, published Dec. 12, 1999. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/142,561, filed Jul. 7, 1999; herein incorporated in its entirety by reference; as well as copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/145,631, filed Jul. 26, 1999; herein incorporated in its entirety by reference. 
b) Synthesis of xcex1-ketoamide, xcex1-ketoester and xcex1-diketone
xcex1-Ketoamides and other xcex1-keto derivatives are generally introduced in the hydroxy form and then oxidized to the active ketone form in the final synthetic step after coupling to the carboxylic acids 1-6 or 1-8a. Scheme 8 illustrates the synthesis of xcex1-hydroxy esters and xcex1-hydroxy amides. In Scheme 8, substituted acrylate ester 8-1 can be aminohydroxylated using Sharpless""s procedure (Tao, B.; Sharpless, K. B., et. al. Tetrahedron Lett. 1998, 39, 2507-2510) to form Cbz-protected amino alcohol 8-2. Catalytic hydrogenation of 8-2 can give a-hydroxy ester 8-3. Alternatively, 8-2 can be hydrolyzed to tree acid 8-4 and coupled to amine H2N-Q to give Cbz-protected amino xcex1-hydroxy amide 8-5. Catalytic hydrogenation of 8-5 can give xcex1-hydroxy ketoamide 8-6. For other methods to prepare xcex1-keto esters, amides or other electrophilic carbonyl derivatives, see a. Wasserman, H. H. et al., J. Org. Chem. 1994, 59, 4364; b. Peet, N., et. al. Tetrahedron Lett. 1988, 3433-3436; Edwards, P. D.; Bernstein, P. R. Medicinal Res. Reviews 1994, 14, 127-194, and references cited therein; Sharpless, K. B.; et. al., Angew. Chem. Int. Ed. Engl. 1996, 35, 451; and Sharpless, K. B. et. al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2813. Many of the xcex1,xcex2-unsaturated esters, 8-1, are commercially available or may be easily prepared from commercially available materials.
Amines of the formula H2N-Q can be prepared from commercially available materials by methods known to one skilled in the art of organic synthesis. More preferably, see techniques disclosed in copending commonly assigned U.S. Provisional Patent Application U.S. Ser. No. 60/168,998, filed Dec. 3, 1999; herein incorporated in its entirety by reference. 
xcex1-Hydroxyl xcex2-amino esters can also be prepared by the method outlined in Scheme 8A. Treatment of phosphonoglycine trimethyl ester 8-7, wherein Zxe2x80x3 is an amino protecting group such as CBZ, with difluoroacetaldehyde hemiacetal 8-8 in the present of KOtBu yields xcex1,xcex2-unsaturated esters 8-9. Hydrogenation of 8-9 in the present of a chiral Rh catalyst, such as Duphos, can selectively reduce the double bond and afford 8-10 in high enantiomeric excess. DIBAL reduction of methyl esters 8-10 can give corresponding aldehyde 8-11, which under the treatment of lithium tris(methylthhio)methane to provide xcex1-hydroxyl compound 8-12. Finally, xcex1-hydroxyl xcex2-amino esters of formula 8-13 can be obtained when 8-12 is treated with Hg2+ (Kaneko, S. K.; et. al., J. Org. Chem. 1993, 58, 2302). Free amine 8-14 can be formed by deprotection of Cbz group under hydrogenation conditions. 
c) Synthesis of Amino Trifluoromethyl and Pentafluoroethyl Ketones.
Similar to xcex1-ketoamides and other xcex1-keto derivatives, the trifluoromethyl or pentafluoroethyl ketone functionality is also introduced in the hydroxy form and oxidized to the active ketone form in the final step. Scheme 9 illustrates the synthesis of amino trifluoromethyl alcohol (Skiles, J. W.; et. al. J. Med. Chem. 1992, 35, 641-662) and amino pentafluoroethyl alcohol (Ogilvie, W. et. al J. Med. Chem. 1997, 40, 4113-4135). In Scheme 9, a Henry reaction between a nitroalkane R1NO2 and trifluoroacetaldehyde ethyl hemiacetal can afford nitro alcohol 9-1, which can be hydrogenated over Raxe2x80x94Ni. The resulting amino alcohol 9-2 can be converted to the N-Boc derivative 9-3. Alternative ways to make 9-3 include treatment of 9-3a with trifluoromethyl trimethylsilane, phenyl trifluoromethyl sulphide, or trifluoromethyl halide. (a. Walter, M. W.; Adlington, R. M.; Baldwin, J. E.; Schofield, C. J. Tetrahedron 1997, 53 (21), 7275-7290; b. Yokoyama, Y.; Mochida, K.; Synlett 1996, 12, 1191-1192; c. Kitazume, T.; Ishikawa, N.; J Am Chem Soc 1985, 107, 5186). Many xcex1-aminoaldehydes, 9-3a, are commercially available or may be easily prepared from commercially available materials by methods known to one skilled in the art of organic synthesis (For preparation of xcex1-aminoaldehydes, see Fukuyama, T., et. al. J. Am. Chem. Soc. 1990, 112, 7050-7051 and Scheidt, K. A., et. al. Bioorg. Med. Chem. 1998, 6, 2477-2499). Treatment of the Boc-amine, 9-3, with anhydrous HCl affords the hydrochloric acid salt 9-4. A solid-phase synthesis of peptidyl trifluoromethyl ketones is also known (Poupart, M. -A., et. al. J. Org. Chem. 1999, 64, 1356-1361). 
Alternatively, condensation of the Weinreb amide 9-5 with CF3CF2Li followed by reduction with NaBH4 can give pentafluoroethyl substituted alcohol 9-6 (Scheme 9A). Deprotection of 9-6 can gives the amino alcohol salt 9-7. Similar to the trifluoromethyl analogs, 9-6 can also be prepared from 9-6a by treatment with trifluoromethyl trimethylsilane, phenyl trifluoromethyl sulphide, or trifluoromethyl halide (Watanabe, S.; Fujita, T.; Sakamoto, M.; Mino, Y.; Kitazume, T. J. Fluorine Chem. 1995, 73 (1), 21-26). 
d) Synthesis of Difluoro xcex2-ketoamide
Scheme 10 outlines the synthesis of hydroxy difluoro xcex2-ketoamides (Veale, C. A., et. al. J. Med. Chem. 1997, 40, 3173-3181; Wolfe, M. S., et. al. J. Med. Chem1998, 41, 6-9). In Scheme 10, protected aminoaldehyde 10-1 (see preparation of 9-3a described above) is reacted with 2-bromo-2,2-difluoroacetate to produce difluoro alcohol 10-2. The alcohol 10-2 can be hydrolyzed to the acid and coupled to an amine H2N-Q to give 10-3. The nitrogen protecting group Pg can be removed according to procedures known to one skilled in the art (Greene, T. W. in Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Ed, 1991), producing the difluoro xcex2-hydroxyamide 10-4. 
e) Synthesis of xcex1-Amino Acids, xcex1-Amino Esters and xcex2-Amino Alcohols
Many xcex1-amino acids and esters, 11-1, are commercially available or may be easily prepared from commercially available materials. For other methods to prepare xcex1-aminoacids or esters, see WO 200009543 and WO 200009558, filed Aug. 9, 2000; herein incorporated in their entirety by reference. 
When R in 11-1 is not a proton, the resulting inhibitors 1-7 to 1-9 from the peptide coupling, such as 1-7 with 11-1, can be obtained from conversions of the esters of structures 1-7 to 1-9 to the corresponding acids (Greene, T. W. in Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Ed, 1991).
Scheme 11 outlines the synthesis of xcex2-amino alcohols and O-protected xcex2-amino alcohols. The nitrogen protecting group Pg can be added and removed, as well as the oxygen protecting group Pgxe2x80x2 can be added and removed, according to procedures known to one skilled in the art (Greene, T. W. in Protective Groups in Organic Synthesis, John Wiley and Sons, 2nd Ed, 1991). N-protections of 11-1 can provide 11-2, which can be reduced to alcohols 11-3 (Larock, R. C. in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, Inc, 1989 and references therein). O-protections of 11-3 can provide 11-4, which can undergo N-deprotections afford O-protected xcex2-amino alcohols 11-5. N-Deprotections of 11-3 can produce xcex2-amino alcohols 11-6. 
The serine traps described above are generally coupled to the free acids 1-6,1-8a, 2-2,2-2a, 1-3, or 2-4 using known peptide coupling procedures (Carpino, et. al. J. Chem. Soc., Chem. Commun. 1994, 201-203). The alcohol functionality of the hydroxy serine trap is oxidized by procedures known to those skilled in the art, such as Dess-Martin periodinane method (Dess, D. 1; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156) in the final step to give a compound of structures 1-7 to 1-9 wherein W contains an activated carbonyl. The alcohol functionality of the hydroxy serine trap in some of structures 1-7 and 3-2 needs to be protected and then deprotected in order to prepare the final compounds 1-7 and 1-9.
When required, separation of racemic materials can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride (Steven D. Young, et. al., Antimicrobial Agents and Chemotheraphy 1995, 2602-2605). Chiral compouns may also be directly synthesized using chiral catalysts or chiral ligands (Andrew S. Thompson, et. al., Tet. Lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.